SHORT COMMUNICATION

DOI: 10.1002/ejoc.201001495

Highly Stereoselective Trichloromethylation of N-(tert-Butylsulfinyl)aldimines:Facile Synthesis of Chiral α-Trichloromethylamines

Ya Li,*[a] Yunlv Cao,[a] Jiaying Gu,[a] Wei Wang,[a] Han Wang,[a] Tao Zheng,[a] andZhihua Sun*[a,b]

Keywords: Sulfur / Amines / Nucleophilic addition / Diastereoselectivity / Trichloromethylation

The first highly stereoselective and facile synthesis ofα-trichloromethylamines is described by using a nucleophilictrichloromethylation strategy. With tetrabutylammonium tri-phenyldifluorosilicate (TBAT) as the mediator, the tri-

IntroductionThe trichloromethyl unit is a structural feature present in

a vast number of bioactive natural products and pharma-ceutical drugs, and it was found to be the key componentfor potent activity and low toxicity in some cases.[1] In thiscontext, α-trichloromethylamines are attracting enormousrecent attention in the field of medicinal chemistry as wellas synthetic chemistry.[2] It was believed that incorporationof the α-trichloromethylamine subunit can result in highermetabolism and improved biological properties of a targetdrug candidate.[2a,2b] Moreover, the α-trichloromethylaminesubunit is highly valuable synthetic intermediate in organicsynthesis, which has frequently served as a precursor for thesynthesis of α-amino acids,[3] 2,2-dichloroaziridines,[4] α-di-and monochloromethylamines,[5] 3,3-dichloropyrrolidines,[6]

along with trichloromethylated heterocyclic compounds.[7]

Despite its importance for applications related to life sci-ences, the synthesis of α-trichloromethylamines has notbeen well explored. The few known methods are mainlybased on the use of a trichloromethyl anion equivalent(“CCl3–”), including trichloroacetic acid,[8] trichlorometh-ane,[9] carbon tetrachloride,[10] or 2,2,2-trichloroethaniminederivatives[11] as precursors. The earliest reported methodfor the preparation of α-trichloromethylamines involved theaddition reaction between trichloroacetic acid and im-ines.[8a,8b] Friedel–Crafts-type reaction of N-(2,2,2-trichlo-

[a] College of Chemistry and Chemical Engineering, ShanghaiUniversity of Engineering Science333 Longteng Road, Shanghai 201620, ChinaFax: +86-21-67791432E-mail: ya.li@sues.edu.cn

sungaris@gmail.com[b] State Laboratory of Drug Research, Shanghai Institute of

Materia Medica, Chinese Academy of SciencesShanghai 201620, ChinaSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201001495.

© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2011, 676–679676

chloromethyl anion (CCl3–) from TMSCCl3 can be transferredto N-(tert-butylsulfinyl)aldimines in excellent yields and withhigh diastereoselectivity (�99:1dr).

roethylidene)benzenesulfonamide with pyrrole or pyrazoleafforded the expected addition products.[11a,12] However,these methods suffer from low yields and lack generality.More recently, Abbaspour Tehrani reported a facial synthe-sis of α,β-unsaturated α-trichloromethylamines by Lewisacid promoted Petasis-type reaction of 2,2,2-trichloroethan-imines with styryl- or phenylethynyltrifluoroborates.[13] Asto the asymmetric synthesis of α-trichloromethylamines,only two examples have been disclosed: one was using theaddition reaction between in situ generated N-acyl-N-(2,2,2-trichloroethylidene)amines and the cyclic enamine(S)-1-(cyclohexenyl)-2-(methoxymethyl)pyrrolidene,[14] andthe other involved ring opening of 3-trichloromethyl β-sul-tam by using alcohols or amines to afford β-trichloromethylβ-amino sulfonates or sulfonamides.[2c] To the best of ourknowledge, there is no general method available for thehighly stereoselective synthesis of α-trichloromethylaminesby using a direct trichloromethylation strategy, and the ge-neral and efficient asymmetric synthesis of α-trichlorome-thylamines still remains an unexplored research area. Aspart of our continuing efforts in the development of ef-ficient methodologies for the synthesis of chiral α-(haloge-nated methyl)amines,[15] herein we report the first stereose-lective synthesis of α-trichloromethylamines by using read-ily accessible trimethyl(trichloromethyl)silane (TMSCCl3,1).

Results and Discussion

In previous reports, TMSCCl3 (1) turned out to be anespecially useful trichloromethylating reagent for carbonylcompounds,[16] commonly accomplished under variousfluoride (F–) sources [tris(diethylamino)sulfonium difluo-romethylsilicate (TASF), potassium fluoride (KF), and tet-rabutylammonium fluoride (TBAF)] or weak Lewis bases

Synthesis of Chiral α-Trichloromethylamines

[potassium carbonate (K2CO3), sodium formate(HCOONa), and so on]. It was observed that the tri-chloromethyl anion (CCl3–), generated in situ from 1 and abase showed both higher thermal stability and better nu-cleophilicity in comparison to trichloromethyllithium(CCl3Li).[17] Although its addition reaction to carbonylcompounds has been extensively explored, only one reportdealing with its addition to imines has appeared in the lit-erature (trichloromethylation of salicylaldimines throughinitial formation of an intramolecular boron complex fol-lowed by interaction with TMSCCl3 gave the tri-chloromethylated adducts in only 34% yield).[18] We envi-sioned that the reactions between TMSCCl3 and chiral im-ines, such as widely used N-(tert-butylsulfinyl)aldimines,would provide an excellent approach to obtain chiral α-tri-chloromethylamines by taking advantage of the reasonablestability of the CCl3– anion and its the high electrophilicproperties and the powerful chiral directing ability of N-(tert-butylsulfinyl)aldimines. With these in mind, first wetried the diastereoselective nucleophilic trichloromethyl-ation of (R)-(tert-butylsulfinyl)aldimine 2a with reagent 1.When compound 1 (1.1 equiv., in THF) was added to asolution of aldimine 2a (1 equiv.) and CsF (0.5 equiv.) inTHF at 0 °C, a facial addition reaction occurred, and corre-sponding products 3a + 3a� can be obtained in 35% yield(Scheme 1). More interestingly, analysis of the crude reac-tion mixture and the obtained product by 1H NMR spec-troscopy showed that the reaction proceeded diastereoselec-tively with 4:1dr.

Scheme 1. Trichloromethylation of 2a by using CsF as the media-tor.

Encouraged by the above results, we then carried out aseries of experiments to improve both the yield and dia-stereoselectivity. Aldimine 2a was used as a model com-pound, and the reaction conditions were carefully tuned asshown in Table 1. It is apparent that the reaction was signif-icantly influenced by the fluoride source, the reaction sol-vent, and the reaction temperature. Using CsF as the fluo-ride source, and less polar to polar solvents, such as di-glyme, THF, and DMF, expected product 2a can only beobtained in 30–67% yield (Table 1, Entries 1–3). After sev-eral trials, we found that the combination of THF andTBAT (tetrabutylammonium triphenyldifluorosilicate)could give better yield and excellent diastereoselectivity(Table 1, Entries 4–7). It is worthy to note that 1.0 equiv. ofTBAT is used to ensure complete conversion of reagent 2a.Also, temperature is important and a lower temperature ishelpful for higher yield (Table 1, Entries 5 and 6). The bestyield and diastereoselectivity were reached with 1.5 equiv.of TMSCCl3 and 1.0 equiv. of TBAT in THF solution at–60 °C (Table 1, Entry 7).

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Table 1. Survey of the reaction conditions.

Entry Fluoride source Solvent T dr[a] Yield(equiv.) [°C] [%][b]

1 CsF (1.1) DMF –20 82:18 302 CsF (1.1) THF –20 80:20 673 CsF (1.1) diglyme –20 85:15 504 TBAT (0.5) THF –20 99:1 525 TBAT (1.0) THF –20 99:1 716 TBAT (1.0) THF –60 99:1 83

7[c] TBAT (1.0) THF –60 99:1 94

[a] Determined by 1H NMR spectroscopy and HPLC analysis ofthe crude product. [b] Isolated yield (3a + 3a�). [c] 1.5 equiv. ofTMSCCl3 was used.

Eventually, the above conditions were applied to a widearray of structurally diverse imines as summarized inTable 2. A remarkable feature of this reaction is that it canbe applied to non-enolizable, enolizable, aromatic, and het-erocyclic imines alike. High diastereoselectivity was ob-served in each case, and good to excellent yields were ob-tained with non-enolizable imines (Table 2, Entries 1–10)and with imines that bear only one α-hydrogen atom(Table 2, Entry 11). Note that the electronic withdrawing/donating nature of the substituent on the aromatic ring hadan undetectable effect on both the yield and diastereoselec-tivity. However, relatively lower yields (35 %) were obtainedin the case of imine 2l, which bears two α-hydrogen atoms(Table 2, entry 12). Careful TLC analysis revealed that im-ine 2l disappeared shortly after the reaction was performedand indicates a labile enolization of 2l under such basic con-ditions. On the other hand, relatively lower diastereoselec-tivities were obtained for all entries when CsF was usedas the fluoride source (Table 2, values in parentheses). Thefluoride difference upon diastereoselectivities appears to bedue to the steric bulk of tetrabutylammonium counterion,which played an important role in the trichloromethyltransfer process.[19]

The absolute configuration of sulfinamide 3a was deter-mined by single-crystal X-ray analysis (Figure 1a), and wasconsistent with our prediction based on a commonly usednonchelation-controlled transition-state mode to give theCram products (Figure 1b), in which the tert-butyl groupadopts the antiperiplanar arrangement with respect to theC=N bond.[15,20] However, recent studies indicated that,mainly due to the contribution of intramolecular hydrogenbonding of the oxygen with the imine hydrogen, the sulfinyloxygen in a s-cis arrangement with respect to the C=Nbond is the most stable conformation for the N-(phenylsulf-inyl)imine.[21] The approach of the nucleophile (CCl3–) tothis conformation would also lead to the observed stereose-lectivity as shown in Figure 1c. We tentatively assume thatone or both transition-state modes are involved in this tri-chloromethylation reaction. The configurations of 3b–lwere assigned by analogy.

Y. Li, Y. Cao, J. Gu, W. Wang, H. Wang, T. Zheng, Z. SunSHORT COMMUNICATIONTable 2. Trichloromethylation of N-(tert-butylsulfinyl)aldimines 2by using TMSCCl3 (1).

[a] Yield of isolated pure material. [b] The dr values in parenthesesare those obtained with CsF as the fluoride source. [c] Determinedby 1H NMR spectroscopy and HPLC analysis of the crude reactionmixture. For more details, see the Supporting Information.

In 2001 Prakash, Olah, and co-workers reported an ele-gant diastereoselective nucleophilic trifluoromethylation ofN-(tert-butylsulfinyl)imines using the Ruppert–Prakash rea-gent (TMSCF3).[19a] Compared to the trifluoromethyl anion(CF3

–) (generated from TMSCF3 in the presence of a fluo-ride activator), the trichloromethyl anion (CCl3–) showedsimilar reactivity: both of which worked better for non-en-olizable imines than enolizable ones.

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Figure 1. The X-ray crystal structure of 3a (a) and depiction of itsstereoselective formation (b, c).

The tBuS(O) group can be easily removed following re-ported procedures without affecting the trichloromethylgroup.[20] For instance, compound 3a was subject to acid-catalyzed alcoholysis with HCl/MeOH to afford α-tri-chloromethyl 2-benzenemethanamine 4 in near-quantitativeyield (Scheme 2). To ensure that there was no racemizationduring the deprotection process, we converted amine salt 4into benzamide derivative 5. The optical purity of 5(99 %ee), determined by chiral HPLC, indicated that theabove deprotection procedure was reliable for the prepara-tion of enantiomerically pure α-trichloromethylamines.

Scheme 2. Conversion of 3a into amine salt 4 and benzamide deriv-ative 5.

Conclusions

In summary, we have successfully developed the firsthighly stereoselective and facile synthesis of α-trichlorome-thylamines by using a straightforward trichloromethylationstrategy. Trichloromethylation of (R)-(N-tert-butylsulfinyl)-aldimines with trimethyl(trichloromethyl)silane (TMSCCl3)affords the corresponding products in excellent yields andwith high diastereoselectivity (�99% dr). Facile and conve-nient deprotection of the tert-butylsulfinyl group gives thetarget trichloromethylamines in quantitative yield withoutaffecting the trichloromethyl group. The synthetic applica-tions of α-trichloromethylamines are still under investiga-tion in our lab.

Synthesis of Chiral α-Trichloromethylamines

Experimental SectionGeneral Procedure for the Trichloromethylation of Imines by usingTMSCCl3 (1): TMSCCl3 (1; 1.5 equiv., 1.5 mmol) in THF (3 mL)was added to a mixture of imine 2 (1 mmol) and TBAT (1 equiv.,1 mmol) in THF (8 mL) at –60 °C. The reaction mixture was stirredfor 1 h. Then, a half-saturated NH4Cl/H2O solution (2 mL) wasadded at low temperature, and the quenched reaction mixture wasextracted with ethyl acetate (3�). The combined organic layerswere dried with anhydrous MgSO4. Evaporation of the solvent af-forded the crude product, which was subjected to flash chromatog-raphy to give the corresponding sulfonamide 3.

CCDC-784869 (for 3a) contains the supplementary crystallo-graphic data for this paper. These data can be obtained free ofcharge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.

Supporting Information (see footnote on the first page of this arti-cle): Experimental details, characterization data, and copies of the1H and 13C NMR spectra of the new compounds.

Acknowledgments

Financial support by Shanghai University of Engineering Scienceand State Laboratory of Drug Research (CAS) are gratefully ac-knowledged.

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Received: November 6, 2010Published Online: December 17, 2010